The naturally occurring prostaglandins are comprised of several biological entities including prostaglandin E (PGE). Prostaglandin E2 (abbreviated as PGE2 herein) is known to be a cyclooxygenase induced oxidative metabolite in the arachidonic acid cascade, and it has been well documented that prostaglandins, including PGE2, have effects on many of the organs and systems of the body. For example, it is known that PGE2 has cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a sleep-inducing effect, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity. In previous studies it has been found that the PGE2 receptor has various subtypes, each possessing differing physiological roles. At this time, it is known that the PGE2 receptor has four primary subtypes denoted EP1, EP2, EP3 and EP4, each of which mediates different effects in various tissues and cells (Coleman, R. A. et al., Pharm. Rev. 1994, 46(2), 205-229). The EP4 receptor is distributed in such organs as the thymus, heart, kidney, liver, intestine, womb, ductus arteriosus and bone, and it is known that the EP4 receptor is related to relaxation of smooth muscle, differentiation and proliferation of lymphocytes, proliferation of mesangial cells, and collagen production of the fibroblasts. In both the pig and the dog, modulation of the EP4 receptor has been characterized with relaxation of the saphenous vein, and in the rabbit relaxation of the jugular vein occurs (Coleman, R. A. et al., Prostaglandins 1994, 47, 151).
The EP4 receptor is also expressed in the ductus arteriosus (Bhattacharya, M. et al., Circulation 1999, 100, 1751-1756). The ductus arteriosus is an arterial connection in the fetus, which directs blood away from the pulmonary circulation and towards the placenta where oxygenation occurs (Heymann, M. A.; Rudolph, A. M. Physiol. Rev. 1975, 55, 62-78). In one proposed model the EP4 receptor in the ductus arteriosus acts as a sensor that responds to the perinatal drop in circulating levels of PGE2 by triggering closure of the ductus arteriosus (Nguyen, M. et al., Nature 1997, 390, 78-81). Closure of the ductus arteriosus was observed in an in vivo fetal sheep model after administration of a selective EP4 antagonist (PCT International Application WO 01/42281, published on Jun. 14, 2001). Maintaining the ductus arteriosus in the open, or patent state is desirable in the fetus and in infants with certain types of congenital heart defects where pulmonary or systemic blood flow depends on patency of the ductus arteriosus. Maintaining patency of the ductus arteriosus in infants with certain other types of congenital heart disease such as coarctation of the aorta, transposition of the great arteries, and Ebstein's anomaly may also be desirable. For example, infants with coarctation of the aorta, a condition constituting 7% to 8% of congenital cardiac defects, may have sudden onset of heart failure, cardiovascular collapse, and severe metabolic acidosis as the ductus arteriosus closes and distal perfusion is compromised. In cases such as these, PGE1 infusions have been utilized to reopen and maintain the patency of the ductus arteriosus prior to surgical repair of the defect.
An excess of aqueous humor in the anterior chamber of the eye can result in elevated intraocular pressure or ocular hypertension. Ocular hypertension is a symptom and/or risk factor for glaucoma, a disease that can damage the optic nerve and cause blindness. The EP4 receptor has been found in ocular tissues involved in the production of the aqueous humor, such as human ciliary epithelial cells and human ciliary muscle cells (Mukhopadhyay et al., Biochem. Pharmacol. 1997, 53, 1249-1255). Trabecular meshwork cells are known to be involved in the regulation of intraocular pressure (Clark et al., Investigative Opthalmology & Visual Science 1994, 35, 281-294; and Lutjen-Drescoll, Progress in Retinal and Eye Research 1998, 18, 91-119). The EP4 receptor has also been found in human trabecular meshwork cells and it has been proposed that activation of the EP4 receptors in the trabecular meshwork cells can result in relaxation of these cells, thereby lowering intraocular pressure (PCT International Patent Application WO 00/38667, published on Jul. 6, 2000).
As PGE1 and PGE2 bind to all four of the PGE2 receptor subtypes (EP1, EP2, EP3, and EP4), various physiological activities may result, some of which may be an undesired side effect due to the lack of selectivity in binding to the PGE2 receptor subtypes. It is therefore desirable to have methods of treatment for various disorders comprising administration of compounds with selectivity to a particular PGE2 receptor subtype.
Great Britain Patent Specification 1 553 595 discloses compounds of the formula
wherein the double bonds are cis or trans and the variables are defined as set forth therein. Those compounds are disclosed as having spasmogenic and spasmolytic activity, for example bronchodilatory and antihypertensive effects. The compounds are also disclosed as having utility in the inhibition of the secretion of gastric juice and as having abortive effects.
U.S. Pat. No. 4,115,401 discloses compound of the formula
wherein the variables are defined as set forth therein. Those compounds are disclosed as having spasmogenic, cardiovascular and bronchodilatory effects.
U.S. Pat. No. 4,113,873 discloses compound of the formula
wherein the variables are defined as set forth therein. Those compounds are disclosed as having utility as a bronchodilator, as an antihypertensive agent, as an enhancer of spontaneous contraction of the uterus and for the treatment of gastro-intestinal disorders or gastric ulcers.
Great Britain Patent Specification 1 583 163 discloses compounds of the formula
wherein the variables are defined as set forth therein. Those compounds are disclosed as having spasmogenic, bronchodilatory, vasoconstricting, vasodilating and abortive properties as well as utility in the inhibition of gastric acid secretion.
U.S. Pat. No. 4,177,346, discloses compounds of the formula
wherein the variables are defined as set forth therein. Those compounds are disclosed as having vasodilator, antihypertensive, bronchodilator, antifertility and antisecretory activity.
U.S. Patent Application Publications Nos. US 2001/0041729, which published on Nov. 15, 2001, and US 2001/0047105, which published on Nov. 29, 2001, disclose methods of treatment with compounds of the formula
wherein the variables are defined as set forth therein. The methods of treatment disclosed in US 2001/0041729 include the treatment of acute or chronic renal failure or dysfunction, or a condition caused thereby, such as hypertension, congestive heart failure, glomerulonephritis, uremia or chronic renal insufficiency. The methods of treatment disclosed in US 2001/0047105 include the treatment of conditions which present with low bone mass, particularly osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth.
U.S. patent application Ser. No. 09/990,556, which was filed on Nov. 21, 2001, discloses compounds of the formula
wherein the variables are as defined therein. The compounds are useful for the treatment of conditions which present with low bone mass such as osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, bone loss associated with periodontis or prosthetic ingrowth.
There exists a continuing need and a continuing search in this field of art for methods of treating hypertension, liver failure, loss of patency of the ductus arteriosus, glaucoma and ocular hypertension. More specifically, there is a need for methods of treating hypertension, liver failure, loss of patency of the ductus arteriosus, glaucoma or ocular hypertension in a patient in need thereof with selective prostaglandin receptor agents that do not have the undesired side effects caused by methods of treatment with non-selective agents.